title: Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones.
abstract: A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.
authors.affiliation: Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061.
authors.forename: J F
authors.initials: JF
authors.lastname: Wolfe
authors.forename: T L
authors.initials: TL
authors.lastname: Rathman
authors.forename: M C
authors.initials: MC
authors.lastname: Sleevi
authors.forename: J A
authors.initials: JA
authors.lastname: Campbell
authors.forename: T D
authors.initials: TD
authors.lastname: Greenwood
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001640:Bicuculline; D055598:Chemical Phenomena; D002621:Chemistry; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D007928:Lethal Dose 50; D008297:Male; D008702:Methaqualone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011725:Pyridines / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D013331:Strychnine
chemical_list: D000927:Anticonvulsants; D001640:Bicuculline; D008702:Methaqualone; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011725:Pyridines; D013331:Strychnine